posted on 2023-12-26, 10:29authored byYazhou Wang, Chao Wang, Tingting Liu, Hongyun Qi, Shan Chen, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Xiao Ding, Alex Zhavoronkov
Breast
and gynecological cancers are among the leading causes of
death in women worldwide, illustrating the urgent need for innovative
treatment options. We identified MYT1 as a promising new therapeutic
target for breast and gynecological cancer using PandaOmics, an AI-driven
target discovery platform. The synthetic lethal relationship of MYT1
in tumor cell lines with CCNE1 amplification enhanced this rationale.
Through structure-based drug design, we developed a series of novel,
potent, and highly selective inhibitors specifically targeting MYT1.
Importantly, our lead compound, featuring a tetrahydropyrazolopyrazine
ring, exhibits remarkable selectivity over WEE1, a related kinase
associated with bone marrow suppression upon inhibition. Optimization
of potency and physical properties resulted in the discovery of compound 21, a novel MYT1 inhibitor, exhibiting optimal pharmacokinetic
properties and promising in vivo antitumor efficacy.